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Elizabeth A. Young, MD; Roger F. Haskett, MD; Leon Grunhaus, MD; Atul Pande, MD; Virginia Murphy Weinberg, RN; Stanley J. Watson, MD, PhD; Huda Akil, PhD

Arch Gen Psychiatry. 1994;51(9):701-707.

Abstract
Objective
To determine whether depressed patients demonstrate hypothalamic-pituitary-adrenal (HPA) axis activation during the late afternoon and evening, a time when the HPA axis is usually quiescent in normal subjects.

Methods
We administered metyrapone, an 11-βhydroxylase inhibitor of cortisol synthesis, to normal controls and depressed patients between 4 and 10 PM. Metyrapone blockade of cortisol secretion would amplify any HPA axis secretion.

Results
In 10 normal control subjects, administration of metyrapone lowered plasma cortisol levels to a mean of 36 nmol/L. No rebound corticotropin or β-endorphin secretion was seen in these normal controls between 4 and 10 PM, supporting the existence of a period of minimal endogenous corticotropin releasing factor drive. Compared with a group of placebo-treated depressed patients (n=10), metyrapone-treated depressed subjects (n=17) had significantly decreased plasma cortisol concentrations. However, in contrast to normal controls treated with metyrapone, metyrapone-treated depressed patients demonstrated rebound corticotroph secretion, particularly between 7:30 and 10 PM (P=.036 for patients vs normal controls for β-endorphin secretion from 4:30 to 10 PM).

Conclusion
These data support the hypothesis of increased corticotropin releasing factor drive in the evening in depressed subjects and are in agreement with the longstanding observation of "early escape" from dexamethasone suppression between 4 and 11 PM in depressed patients.

Author Affiliations
From the Department of Psychiatry and the Mental Health Research Institute, University of Michigan Medical Center, Ann Arbor. Dr Haskett is now with the Department of Psychiatry, Western Psychiatric Institute, Pittsburgh, Pa. Dr Grunhaus is now with the Department of Psychiatry, Sheba Hospital, Tel Hashomer, Israel. Dr Pande is now with eli Lilly Pharmaceuticals, Indianapolis, Ind.

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